tbuckley/cabot-search huggingface dataset:
Registration of essential medicines in Kenya, Tanzania and Uganda: a retrospective analysis
Authors: A Green, R Lyus, M Ocan, AM Pollock, P Brhlikova
Journal: Journal of the Royal Society of Medicine (2023)

Objectives To audit national drug registers (NDRs) in Kenya, United Republic of Tanzania and Uganda with respect to national Essential Medicine Lists (EMLs) and to conduct an analysis of highly registered products including a sub-analysis of highly registered antimicrobial products. Design Retrospective analysis of registration of essential medicines and medicinal products on NDRs as of February 2018. Setting Not applicable. Participants None. Main outcome measures Registration status of essential medicines by country, essential medicine status of registered products by country and medicines with more than 50 registrations across all three countries. Results A high proportion of essential medicines are not registered: Kenya 28% (175/632), United Republic of Tanzania 50% (400/797) and Uganda 40% (266/663). Of registered products on the NDRs, more than half are not essential: Kenya 71% (4350/6151), United Republic of Tanzania 64% (2278/3590) and Uganda 58% (2268/3896). When the three NDRs were combined, there were 42 medicines with over 50 registered products, accounting for 30% (4153/13637) of products, many of which were non-essential. Conclusions Non-registration of essential medicines is a barrier to availability. Over-registration of medicines, particularly non-essential medicines, diverts regulatory resources towards registering non-priority and, sometimes, clinically sub-optimal medicines. The East African Community Medicines Registration Harmonization Project has the potential to improve access to key medicines if registration of essential medicines is prioritised and registration of non-essential medicines is restricted.
Association between surgeon volume and patient outcomes after elective shoulder replacement surgery using data from the National Joint Registry and Hospital Episode Statistics for England: population based cohort study
Authors: Epaminondas Markos Valsamis, Gary S Collins, Rafael Pinedo-Villanueva, Michael R Whitehouse, Amar Rangan, Adrian Sayers, Jonathan L Rees
Journal: BMJ (2023)

To investigate the association between surgeon volume and patient outcomes after elective shoulder replacement surgery to improve patient outcomes and inform future resource planning for joint replacement surgery.Prospective cohort study.Public and private hospitals in the United Kingdom, 2012-20.Adults aged 18 years or older who had shoulder replacement surgery, identified in the National Joint Registry, with linkage of participants in England to Hospital Episode Statistics data.The main outcome measure was revision surgery. Secondary outcome measures were reoperation within 12 months, serious adverse events, and prolonged hospital stay (>3 nights) after shoulder replacement surgery.39 281 shoulder replacement procedures undertaken by 638 consultant surgeons at 416 surgical units met the inclusion criteria and were available for analysis. Multilevel mixed effects models and restricted cubic splines were fit to examine the association between a surgeon's mean annual volume and risk of adverse patient outcomes, with a minimum volume threshold of 10.4 procedures yearly identified. Below this threshold the risk of revision surgery was significantly increased, as much as twice that of surgeons with the lowest risk (hazard ratio 1.94, 95% confidence interval 1.27 to 2.97). A greater mean annual surgical volume was also associated with a significantly lower risk of reoperations, fewer serious adverse events, and shorter hospital stay, with no thresholds identified. Annual variation in surgeon volume was not associated with any of the outcomes assessed.In the healthcare system represented by these registry data, an association was found between surgeons who averaged more than 10.4 shoulder replacements yearly and lower rates of revision surgery and reoperation, lower risk of serious adverse events, and shorter hospital stays. These findings should inform resource planning for surgical services and joint replacement surgery waiting lists and improve patient outcomes after shoulder replacement surgery.
Haemodynamic support for paediatric septic shock: a global perspective
Authors: Suchitra Ranjit, Niranjan Kissoon, Andrew Argent, David Inwald, Andréa Maria Cordeiro Ventura, Roberto Jaborinsky, Jhuma Sankar, Daniela Carla de Souza, Rajeswari Natraj, Claudio Flauzino De Oliveira, Rujipat Samransamruajkit, Muralidharan Jayashree, Luregn J Schlapbach
Journal: The Lancet Child & Adolescent Health (2023)
Metformin Versus Insulin and Risk of Major Congenital Malformations in Pregnancies With Type 2 Diabetes: A Nordic Register-Based Cohort Study
Authors: Lars J. Kjerpeseth, Carolyn E. Cesta, Kari Furu, Anders Engeland, Mika Gissler, Hanne L. Gulseth, Øystein Karlstad, Maarit K. Leinonen, Laura Pazzagli, Helga Zoega, Jacqueline M. Cohen
Journal: Diabetes Care (2023)

OBJECTIVE To assess the risk of major congenital malformations with metformin versus insulin in pregnancies with type 2 diabetes. RESEARCH DESIGN AND METHODS This cohort study used four Nordic countries’ nationwide registers of live and stillborn infants exposed to metformin or insulin during first trimester organogenesis. Main exclusion criteria were type 1 diabetes, polycystic ovary syndrome, fertility treatment, and exposure to other diabetes drugs. Adjusted risk ratios (RRs) and 95% CIs were estimated for any and cardiac malformations. RESULTS Of 3,734,125 infants in the source population, 25,956 were exposed to metformin or insulin in the first trimester, and 4,023 singleton infants were included. A malformation was diagnosed in 147 (4.7%) of 3,145 infants with exposure to any metformin (alone or in addition to insulin) and 50 (5.7%) of 878 infants with exposure to insulin alone (RR 0.84, 95% CI 0.46–1.54). Among 2,852 infants exposed to metformin alone and 293 infants exposed to metformin in addition to insulin 127 (4.4%) and 20 (6.8%), respectively, had a malformation. The adjusted risk was not increased for either metformin alone (0.83, 0.44–1.58) or both metformin and insulin (0.98, 0.56–1.69) versus insulin alone. Corresponding RRs for cardiac malformations were 1.01 (0.55–1.84) for any metformin, 0.92 (0.47–1.81) for metformin alone, and 1.72 (0.76–3.91) for both metformin and insulin. CONCLUSIONS No evidence of an increased malformation risk with metformin versus insulin in the first trimester was found. Results should be interpreted with caution since information on glycemic control was missing.
Dulaglutide and Kidney Function–Related Outcomes in Type 2 Diabetes: A REWIND Post Hoc Analysis
Authors: Fady T. Botros, Hertzel C. Gerstein, Raleigh Malik, Claudia Nicolay, Anastasia Hoover, Ibrahim Turfanda, Helen M. Colhoun, Jonathan E. Shaw
Journal: Diabetes Care (2023)

Dulaglutide (DU) 1.5 mg was associated with improved composite renal outcomes that included new-onset macroalbuminuria in people with type 2 diabetes with previous cardiovascular disease or cardiovascular risk factors in the REWIND (Researching cardiovascular Events with a Weekly INcretin in Diabetes) trial. This exploratory post hoc analysis evaluated kidney function-related outcomes, excluding the new-onset macroalbuminuria component, among the REWIND participants.Intent-to-treat analyses were performed on REWIND participants (n = 4,949 DU, n = 4,952 placebo). Time to occurrence of a composite kidney function-related outcome (≥40% sustained decline in estimated glomerular filtration rate [eGFR], per the Chronic Kidney Disease Epidemiology Collaboration 2009 equation, end-stage renal disease, or renal-related death), and mean annual eGFR slope were examined. Analyses were conducted overall and within subgroups defined by baseline urinary albumin-to-creatinine ratio (UACR <30 or ≥30 mg/g) and baseline eGFR (<60 or ≥60 mL/min/1.73 m2).The post hoc composite kidney function-related outcome occurred less frequently among participants assigned to DU than placebo (hazard ratio [HR] 0.75, 95% CI 0.62-0.92, P = 0.004), with no evidence of a differential DU treatment effect by UACR or eGFR subgroup. A ≥40% sustained eGFR decline occurred less frequently among participants assigned to DU than placebo (HR 0.72, 95% CI 0.58-0.88, P = 0.002). The mean annual decline in eGFR slope was significantly smaller for participants assigned to DU than placebo (-1.37 vs. -1.56 mL/min/1.73 m2/year, P < 0.001); results were similar for all subgroups.The estimated 25% reduced hazard of a kidney function-related outcome among participants assigned to DU highlights its potential for delaying or slowing the development of diabetic kidney disease in people with type 2 diabetes.
A Short-Form Measure of Diabetes Distress Among Adults With Type 1 Diabetes for Use in Clinical Practice: Development and Validation of the T1-DDS-7
Authors: Mette Nygaard, Ingrid Willaing, Lene Eide Joensen, Pil Lindgreen, Vibeke Stenov, Danielle Hessler, Kirsten Nørgaard, Ulrik Pedersen-Bjergaard, Kasper Olesen
Journal: Diabetes Care (2023)

OBJECTIVE Valid and reliable diabetes distress assessment is essential for identifying adults with elevated levels of concern and to guide targeted support. However, assessing diabetes distress must also be feasible in time-limited settings. We aimed to identify a short-form measure of the 28-item Type 1 Diabetes Distress Scale (T1-DDS-28) representing seven sources of type 1 diabetes distress that would be convenient for use in clinical practice. RESEARCH DESIGN AND METHODS Based on the evaluation of influence and importance by 14 experts in diabetes care and research, we identified the best-performing item within each of seven sources of diabetes distress included in the T1-DDS-28. To further validate the proposed short-form measure, we used survey data from 2,016 adults living with type 1 diabetes. Validity was examined by exploratory factor analysis, Cronbach’s α, test-retest reliability analysis, and correlations with other psychosocial measures. RESULTS We identified a short-form measure of the T1-DDS-28 consisting of seven items, each representing a source of diabetes distress. These items showed satisfactory reliability (factor loadings &amp;gt; 0.45; α = 0.82; test-retest correlation, r = 0.90) and validity (correlation with T1-DDS-28, r = 0.95; area under the curve = 0.91; sensitivity 93%; specificity 89%) when combined in the short-form scale (T1-DDS-7). CONCLUSIONS We propose the T1-DDS-7 as a valid and reliable measure for routine screening of diabetes distress among adults with type 1 diabetes. In case of elevated levels of diabetes distress, we recommend that a full-scale assessment and open dialogue follow the short-form measure before determining further treatment.
Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis
Authors: Javier Bolaños-Meade, Mehdi Hamadani, Juan Wu, Monzr M. Al Malki, Michael J. Martens, Lyndsey Runaas, Hany Elmariah, Andrew R. Rezvani, Mahasweta Gooptu, Karilyn T. Larkin, Brian C. Shaffer, Najla El Jurdi, Alison W. Loren, Melhem Solh, Aric C. Hall, Amin M. Alousi, Omer H. Jamy, Miguel-Angel Perales, Janny M. Yao, Kristy Applegate, Ami S. Bhatt, Leslie S. Kean, Yvonne A. Efebera, Ran Reshef, William Clark, Nancy L. DiFronzo, Eric Leifer, Mary M. Horowitz, Richard J. Jones, Shernan G. Holtan
Journal: New England Journal of Medicine (2023)

In patients undergoing allogeneic hematopoietic stem-cell transplantation (HSCT), a calcineurin inhibitor plus methotrexate has been a standard prophylaxis against graft-versus-host disease (GVHD). A phase 2 study indicated the potential superiority of a post-transplantation regimen of cyclophosphamide, tacrolimus, and mycophenolate mofetil.
Second-Line Switch to Dolutegravir for Treatment of HIV Infection
Authors: Loice A. Ombajo, Jeremy Penner, Joseph Nkuranga, Jared Mecha, Margaret Mburu, Collins Odhiambo, Florentius Ndinya, Rukia Aksam, Richard Njenga, Simon Wahome, Peter Muiruri, Sheila Eshiwani, Maureen Kimani, Catherine Ngugi, Anton Pozniak
Journal: New England Journal of Medicine (2023)

Data to inform the switch from a ritonavir-boosted protease inhibitor (PI) to dolutegravir in patients living with human immunodeficiency virus (HIV) infection who do not have genotype information and who have viral suppression with second-line therapy containing a ritonavir-boosted PI have been limited. Download a PDF of the Research Summary. In a prospective, multicenter, open-label trial conducted at four sites in Kenya, we randomly assigned, in a 1:1 ratio, previously treated patients without genotype information who had viral suppression while receiving treatment containing a ritonavir-boosted PI to either switch to dolutegravir or continue the current regimen. The primary end point was a plasma HIV type 1 RNA level of at least 50 copies per milliliter at week 48, assessed on the basis of the Food and Drug Administration snapshot algorithm. The noninferiority margin for the between-group difference in the percentage of participants who met the primary end point was 4 percentage points. Safety up to week 48 was assessed. A total of 795 participants were enrolled, with 398 assigned to switch to dolutegravir and 397 assigned to continue taking their ritonavir-boosted PI; 791 participants (397 in the dolutegravir group and 394 in the ritonavir-boosted PI group) were included in the intention-to-treat exposed population. At week 48, a total of 20 participants (5.0%) in the dolutegravir group and 20 (5.1%) in the ritonavir-boosted PI group met the primary end point (difference, −0.04 percentage points; 95% confidence interval, −3.1 to 3.0), a result that met the criterion for noninferiority. No mutations conferring resistance to dolutegravir or the ritonavir-boosted PI were detected at the time of treatment failure. The incidence of treatment-related grade 3 or 4 adverse events was similar in the dolutegravir group and the ritonavir-boosted PI group (5.7% and 6.9%, respectively). In previously treated patients with viral suppression for whom there were no data regarding the presence of drug-resistance mutations, dolutegravir treatment was noninferior to a regimen containing a ritonavir-boosted PI when the patients were switched from a ritonavir-boosted PI–based regimen. (Funded by ViiV Healthcare; 2SD ClinicalTrials.gov number, NCT04229290.) QUICK TAKE VIDEO SUMMARYSecond-Line Dolutegravir for HIV Infection 02:13
Systemic Inflammation and Normocytic Anemia in DOCK11 Deficiency
Authors: Jana Block, Christina Rashkova, Irinka Castanon, Samaneh Zoghi, Jessica Platon, Rico C. Ardy, Mitsuhiro Fujiwara, Beatriz Chaves, Rouven Schoppmeyer, Caspar I. van der Made, Raul Jimenez Heredia, Frederike L. Harms, Samin Alavi, Laia Alsina, Paula Sanchez Moreno, Rainiero Ávila Polo, Rocío Cabrera-Pérez, Sevgi Kostel Bal, Laurène Pfajfer, Bernhard Ransmayr, Anna-Katharina Mautner, Ryohei Kondo, Anna Tinnacher, Michael Caldera, Michael Schuster, Cecilia Domínguez Conde, René Platzer, Elisabeth Salzer, Thomas Boyer, Han G. Brunner, Judith E. Nooitgedagt-Frons, Estíbaliz Iglesias, Angela Deyà-Martinez, Marisol Camacho-Lovillo, Jörg Menche, Christoph Bock, Johannes B. Huppa, Winfried F. Pickl, Martin Distel, Jeffrey A. Yoder, David Traver, Karin R. Engelhardt, Tobias Linden, Leo Kager, J. Thomas Hannich, Alexander Hoischen, Sophie Hambleton, Sabine Illsinger, Lydie Da Costa, Kerstin Kutsche, Zahra Chavoshzadeh, Jaap D. van Buul, Jordi Antón, Joan Calzada-Hernández, Olaf Neth, Julien Viaud, Akihiko Nishikimi, Loïc Dupré, Kaan Boztug
Journal: New England Journal of Medicine (2023)

Increasing evidence links genetic defects affecting actin-regulatory proteins to diseases with severe autoimmunity and autoinflammation, yet the underlying molecular mechanisms are poorly understood. Dedicator of cytokinesis 11 (DOCK11) activates the small Rho guanosine triphosphatase (GTPase) cell division cycle 42 (CDC42), a central regulator of actin cytoskeleton dynamics. The role of DOCK11 in human immune-cell function and disease remains unknown.We conducted genetic, immunologic, and molecular assays in four patients from four unrelated families who presented with infections, early-onset severe immune dysregulation, normocytic anemia of variable severity associated with anisopoikilocytosis, and developmental delay. Functional assays were performed in patient-derived cells, as well as in mouse and zebrafish models.We identified rare, X-linked germline mutations in DOCK11 in the patients, leading to a loss of protein expression in two patients and impaired CDC42 activation in all four patients. Patient-derived T cells did not form filopodia and showed abnormal migration. In addition, the patient-derived T cells, as well as the T cells from Dock11-knockout mice, showed overt activation and production of proinflammatory cytokines that were associated with an increased degree of nuclear translocation of nuclear factor of activated T cell 1 (NFATc1). Anemia and aberrant erythrocyte morphologic features were recapitulated in a newly generated dock11-knockout zebrafish model, and anemia was amenable to rescue on ectopic expression of constitutively active CDC42.Germline hemizygous loss-of-function mutations affecting the actin regulator DOCK11 were shown to cause a previously unknown inborn error of hematopoiesis and immunity characterized by severe immune dysregulation and systemic inflammation, recurrent infections, and anemia. (Funded by the European Research Council and others.).
Ensuring Ethical Postprogression Therapy for Patients in Randomized Trial Control Arms
Authors: Edward R. Scheffer Cliff, Aaron S. Kesselheim, William B. Feldman
Journal: Journal of Clinical Oncology (2023)

@Eddie_Cliff et al explore the scientific &amp; ethical reasons why patients randomized to the control arm of trials should 'crossover' to receive the investigational therapy if their disease progresses
Case 19-2023: An 80-Year-Old Man with Left Foot Drop
Authors: Paloma González-Pérez, Karen A. Buch, Reza Sadjadi
Journal: New England Journal of Medicine (2023)

An 80-year-old man was evaluated in the neurology clinic because of left foot drop. There was weakness in facial, periscapular, hip-flexor, and leg muscles. MRI of the spine revealed disk herniation. A diagnosis was made.
Severe Hepatopathy in National Wilms Tumor Studies 3-5: Prevalence, Clinical Features, and Outcomes After Reintroduction of Chemotherapy
Authors: Natanja Oosterom, Saskia L.M. Gooskens, Lindsay A. Renfro, Elizabeth J. Perlman, Marry M. van den Heuvel-Eibrink, Thomas E. Hamilton, Daniel M. Green, Paul E. Grundy, Najat C. Daw, James I. Geller, Jeffrey S. Dome, Conrad V. Fernandez, Elizabeth A. Mullen
Journal: Journal of Clinical Oncology (2023)

The safety of reintroducing chemotherapy in the pediatric renal tumor setting after severe hepatopathy (SH), including sinusoidal obstruction syndrome (SOS), is uncertain. We describe the incidence, severity, outcomes, and impact on subsequent treatment for patients with SH from National Wilms Tumor Study (NWTS) protocols 3-5.
Marburg Virus Disease in Ghana
Authors: Joseph K Bonney, Bright Adu, Terrel Sanders, Deborah Pratt, Patience Adams, Ivy A Asante, Evelyn Y Bonney, Bright Agbodzi, Selassie Kumordjie, Martin Faye, Evangeline Obodai, Prince Ketorwoley, Clara Yeboah, Mildred Tublu, Moussa M Diagne, Amadou Diallo, Magdalene Ofori, Dennis Laryea, Franklin Asiedu-Bekoe, George B Kyei, Sally-Ann Ohene, Gifty Boateng, Ryan Chapman, Ousmane Faye, Michael Wiley, John Odoom, Amadou Sall, Francis C Kasolo, Dorothy Yeboah-Manu
Journal: New England Journal of Medicine (2023)
An improved reporter identifies ruxolitinib as a potent and cardioprotective CaMKII inhibitor
Authors: Oscar E. Reyes Gaido, Nikoleta Pavlaki, Jonathan M. Granger, Olurotimi O. Mesubi, Bian Liu, Brian L. Lin, Alan Long, David Walker, Joshua Mayourian, Kate L. Schole, Chantelle E. Terrillion, Lubika J. Nkashama, Mohit M. Hulsurkar, Lauren E. Dorn, Kimberly M. Ferrero, Richard L. Huganir, Frank U. Müller, Xander H. T. Wehrens, Jun O. Liu, Elizabeth D. Luczak, Vassilios J. Bezzerides, Mark E. Anderson
Journal: Science Translational Medicine (2023)

Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) hyperactivity causes cardiac arrhythmias, a major source of morbidity and mortality worldwide. Despite proven benefits of CaMKII inhibition in numerous preclinical models of heart disease, translation of CaMKII antagonists into humans has been stymied by low potency, toxicity, and an enduring concern for adverse effects on cognition due to an established role of CaMKII in learning and memory. To address these challenges, we asked whether any clinically approved drugs, developed for other purposes, were potent CaMKII inhibitors. For this, we engineered an improved fluorescent reporter, CaMKAR (CaMKII activity reporter), which features superior sensitivity, kinetics, and tractability for high-throughput screening. Using this tool, we carried out a drug repurposing screen (4475 compounds in clinical use) in human cells expressing constitutively active CaMKII. This yielded five previously unrecognized CaMKII inhibitors with clinically relevant potency: ruxolitinib, baricitinib, silmitasertib, crenolanib, and abemaciclib. We found that ruxolitinib, an orally bioavailable and U.S. Food and Drug Administration–approved medication, inhibited CaMKII in cultured cardiomyocytes and in mice. Ruxolitinib abolished arrhythmogenesis in mouse and patient-derived models of CaMKII-driven arrhythmias. A 10-min pretreatment in vivo was sufficient to prevent catecholaminergic polymorphic ventricular tachycardia, a congenital source of pediatric cardiac arrest, and rescue atrial fibrillation, the most common clinical arrhythmia. At cardioprotective doses, ruxolitinib-treated mice did not show any adverse effects in established cognitive assays. Our results support further clinical investigation of ruxolitinib as a potential treatment for cardiac indications.
Efficacy of vibrotactile positional therapy devices on patients with positional obstructive sleep apnoea: a systematic review and meta-analysis
Authors: Abdullah S ALQarni, Chris D Turnbull, Mary J Morrell, Julia L Kelly
Journal: Thorax (2023)

Introduction Vibrotactile positional therapy (PT) devices are a new treatment modality for positional obstructive sleep apnoea (POSA). This review aimed to determine the effect of vibrotactile PT on the Apnoea Hypopnoea Index (AHI) and the percentage of time spent in the supine position (%Tsupine) in patients with POSA, compared with baseline. Secondary aims were to investigate the effect on daytime sleepiness, quality of life and sleep quality. Methods A systematic review and meta-analysis was performed of randomised controlled trials (RCTs) and cohort studies that investigated the effect of vibrotactile PT in POSA patients. Searches were performed via MEDLINE, CENTRAL and Embase up to 29 October 2022. Results 1119 studies were identified, 18 studies met the inclusion criteria (10 RCTs, 8 cohort studies). The use of vibrotactile PT significantly reduced the AHI at follow-up compared with baseline (mean difference (95% CI) −9.19 events/hour (–11.68 to –6.70); p&lt;0.00001). The mean %Tsupine was also significantly reduced (mean difference (95% CI) −32.79% (–38.75% to –26.83%); p&lt;0.00001). The percentage changes in the AHI and %Tsupine were 43% and 70%, respectively. Secondary outcomes were daytime sleepiness, quality of life and sleep indices. These showed minimal change, although follow-up was short. Conclusion Vibrotactile PT devices are effective in treating POSA; reducing both AHI and %Tsupine. The effect on sleep quality, daytime sleepiness and disease-specific quality of life was minimal. However, there were limited data and follow-up was often brief, meaning that further research is needed to determine the effect of vibrotactile PT on patient-centred outcomes. PROSPERO registration number CRD42020188617.